Involvement of endogenous tachykinins in LTD₄-induced airway responses

Leukotriene D₄-(LTD₄) has been reported to cause tachykinin release from airway sensory nerves. However, the functional significance of endogenously released tachykinins in LTD₄-mediated airway responses has not been fully clarified. The aim of this study was to investigate whether LTD₄-induced airway responses are due, in part, to tachykinin release in guinea-pigs. Airway plasma exudation and bronchoconstriction were assessed by measuring extravasation of Evans blue dye and by mean pulmonary resistance (RL) in the presence of atropine (1 mg · kg^-a1 i.v.) and propranolol (1 mg · kg^-1 i.v.), respectively. LTD₄ (5 μg · mL^-1 for 1 min) inhalation caused increase in plasma exudation and RL. Capsaicin pretreatment of animals to deplete sensory neuropeptides significantly inhibited LTD₄-induced plasma exudation in the main bronchi, but not in the central (cIPA) and peripheral intrapulmonary airways (pIPA). Pretreatment with specific tachykinin neurokinin-1 (NK₁)-receptor antagonists. FK 888 (10 mg · kg^-a1 i.v.) and CP 96345 (4 mg · kg^-a1 i.v.), also significantly reduced LTD₄-induced plasma exudation in the main bronchi, and in the main bronchi and cIPA, respectively. However, these antagonists did not significantly affect the LTD₄-induced increase in RL. In contrast, neurokinin-2 (NK₂)-receptor antagonists, SR 48968 (0.3 mg · kg^-1 .v.), significantly inhibited the bronchoconstriction after LTD₄-inhalation. These results suggest that leukotriene D₄-induced bronchoconstriction and plasma exudation in guinea-pigs are, in part, due to tachykinin release from airway sensory nerves.